Stress and the hormone Cortisol
Brian asked me to write about stress. I thought he meant my stress, so I asked if I had 20,000 words to use. I also informed him the finished work would read more like a horror screenplay.
It turns out he felt readers (you) would be bored by reading about my stress, even the time when a Grizzly bear wanted to inflict much harm upon my person. Instead, he suggested, I focus on the myriad health consequences of chronic stress and elevated cortisol levels and how to ameliorate them. I agreed to proceed as long as he told me what ameliorate means (to improve or alleviate a specific condition).
Cortisol and the HPA axis
Hormones are substances (usually proteins but sometimes cholesterol-derived steroids) produced in one part of the body, travel via the bloodstream, and affect cells and organ function elsewhere. They are made in meager amounts from numerous organs and interact with distant tissues via a receptor. Like a lock and key, the hormone's functions initiate once coupled with a receptor. And a wide array of functions there are! Growth and development, metabolism, bone density, immune function and inflammation, bowel function, mood, and even genes' expression are affected by hormones. Essentially, hormones regulate all biological processes in the human body.
The "HPA axis" is the hormonal intersection of the Hypothalamus, Pituitary, and Adrenal glands, serving as the brain/adrenal connection. In this trio, the hypothalamus, a master regulatory center of the brain, releases a hormone called CRH. CRH then takes an exhausting, several-millimeter journey to the pituitary gland and stimulates the release of ACTH. This ACTH acts directly on the adrenal glands, resulting in cortisol release. So chronically elevated cortisol from excessive stress or a crappy diet originates from your brain.
Cortisol is a steroid hormone made from that nasty stuff called cholesterol. Bad cholesterol! Egg whites rule! (just kidding – I love the yolks). Anyway, the outer regions of the adrenal glands, perched on top of the kidneys, produce cortisol. The inner zones of the adrenals create other hormones like epinephrine (adrenaline). The disproportionate influence of the adrenal glands on health and other hormonal imbalances leads many practitioners within functional medicine to adopt the tenet "start with the adrenals" when addressing health problems and health in general.
The release of cortisol follows a rhythm, peaking in the morning known as the Cortisol Awakening Response, part of the Dawn Phenomenon (along with other hormones like glucagon, epinephrine, growth hormone, etc.). Time to get up! This very natural morning state is why low-carb eaters (who are good fat burners) commonly have "elevated" blood sugars in the morning. They get misdiagnosed with pre-diabetes when instead it's Adaptive Glucose Sparing and a natural Hunter-Gatherer place to be-but I digress. Cortisol peaks in the morning and declines throughout the day. At least it should follow that course.
Throughout our human experience, we have developed a sophisticated system for handling stressful situations of shorter duration like being mauled by some long-ago extinct predator, injury, clan gossip, or food scarcity. Many feel we are chemically less adept at dealing with our modern environment's constant and ongoing stress and longer lifespans. This lack of stress-reprieve is considered by many to be a significant contributor to numerous diseases.
Relatively small and temporary deviations from that pattern are common. Acute (traffic or a poor night's sleep) and chronic stress (ongoing stress from a medical disease, hating your job, dysfunctional marriage, politics) affect cortisol levels. Over time, heightened cortisol levels detrimentally impact numerous body systems, including mental health, sleep-wake cycles, bone density, blood pressure, body weight, cravings, blood sugar, and inflammatory levels - all of which are important.
The extent of testing for cortisol in Western Medicine usually involves investigation for suspected Cushings Disease and Addison's Disease. These are severe medical diseases of massive overproduction and underproduction of cortisol, respectively. Both are very uncommon conditions. However, disruptions to the HPA-axis and cortisol deviations from a regular pattern are more common. Mention this at your next exam, and your primary care provider's eyes will likely gloss over. He/she/they were not trained this way.
Anything that stresses the body may distort the curve: Injuries, over-training, infections, dysbiosis (distorted gut microbiome), toxins, food sensitivities/allergies, poor diet, and of course, emotional stress. There are several potential distorted curve patterns, and four-point testing is required to identify them. Testing is best performed on your own, using widely available saliva kits. Ideally, a Functional Medicine trained provider or Naturopathic Physician would help you interpret the results and offer personalized treatments. However, many interventions apply to almost everyone that can help restore normalcy to your freaky weird curve. I will touch on these modalities later.
One reasonably common cortisol curve variant is a flat curve that does not decrease appropriately but is continually elevated. Kumari et al (J Clin Endocrinol Metab 2011) found that this pattern was associated with increased all-cause mortality, including cardiovascular deaths.
Salivary testing is convenient, inexpensive, noninvasive, and accurate, particularly for cholesterol-derived hormones like cortisol. Furthermore, there is a strong correlation between salivary hormone levels and the blood levels of the hormone in its free/active/bio-available form. Collect saliva in the morning, upon waking. Again at noon, 4 pm, and before bed. Thus "four-point." You spit into a container four times, get it?
The closest thing to four-point salivary testing I do in the office is two separate blood tests, at around 8 am and 4 pm. Call it a poor man's four-point test, though a misnomer because it's way more expensive. Typical ranges in the morning are 10-20 mcg/dL and at 4 pm 3-10 mcg/dL. The morning value really should be a few points higher than the afternoon value, or you're likely dealing with a flat curve. For me, this acts as a general screen of the HPA axis. If abnormal, I urge further study with saliva testing.
Cortisol and weight gain
A few studies agree that 70% of us will increase food intake when faced with stress, and 30% will take in less. But, like most human things, these diverging behaviors interplay between physiology (our cellular functioning) and psychology (our culture, upbringing, and what we're taught). Stress eating increases in those diagnosed with obesity, particularly those with high "cortisol reactivity ."Herhaus et al (Translational Psychiatry Jan 2020) showed that patients with obesity with the highest cortisol release in response to stress were more vehemently driven to consume comfort foods, which of course, makes this very challenging disease even harder to treat. In addition, there are many neurologic and hormonal distortions within obesity that leaner-weight individuals do not possess, and distortion within the HPA axis is but one example. And for me, this underscores a necessity for treating obesity with medications.
Not everyone reacts the same to stress. Some dump cortisol, others exhibit small elevations. For example, Epel et al (Psychoneuroendocrinology Jan 2001) studied 59 healthy pre-menopausal women. Those that reacted to stress by releasing more cortisol ate considerably more calories, particularly sweets. You and I both know by now that insulin levels will surge over time, and the cascade of dysfunction resulting in obesity is well underway.
Steptoe et al (Int J Obes Relat Metab Disord Sept 2004) showed that men with the highest cortisol levels also had the most unfavorable waist/hip ratio (a measure of abdominal obesity). They also had the most unfavorable cholesterol panels (low good cholesterol and high total cholesterol/HDL ratio, both of which are unfavorable). As I've previously written, I see several male endurance athletes in their 30's and 40's. They want to know why they have a gut. It's inexplicable to them, given the amount of exercise they perform. Most follow a script-they train and race fueling with simple sugars. They eat carbohydrates throughout the day and commonly drink beer. With elevated cortisol, their diet worsens their condition, given their anthropologically abnormal exertion levels. Cortisol readily interacts with abdominal white adipose tissue, and the gut develops. Aside from not liking it, their risk of heart disease and cancers is elevated with a suboptimal power to weight ratio, and consequently, they are not performing at their best.
Gyllenhammer et al (not affiliated with Hammer Nutrition), as published in Obesity Feb 2014, showed a strong association between cortisol and visceral adipose tissue (VAT). VAT is fat in and around the organs of our abdomen and is very unfavorable if not dying is something you desire. This study was performed at USC and involved 165 adolescents. Yep, young 'uns. Remember that lock and key analogy? VAT has a much higher concentration of cortisol receptors than other fat tissue. This high capacity to interface with cortisol has led researchers to hypothesize that cortisol can induce fat hypertrophy. "This nuanced relationship between stress pathways and fat deposition or metabolic health may be dependent upon environmental factors, such as dietary intake," the authors state. The study showed significantly higher cortisol and higher belly fat accumulation in the youths that consumed the most sugar. Other interesting findings from the USC study were that fat and protein consumption did not spike cortisol, and omega-3 supplementation was protective against VAT accumulation.
Below are just a few studied treatment modalities to regulate the HPA axis. Numerous supplements (like omega-3 mentioned above) have also been studied but are not listed.
Rodent studies show that sugar consumption reduced cortisol, reinforcing chronic sugar overconsumption. Tyron et al in 2015 (as published in The Journal of Clinical Endocrinology and Metabolism) showed in humans the power of sucrose (sugar) sweetened beverages at quickly reducing the stress hormone cortisol. One of the researchers, Dr. Laugero, states, "The concern is psychological or emotional stress could trigger the habitual overconsumption of sugar and amplify sugar's detrimental effects, including obesity." Let's add that to the list of sugar detriments-Sugar-Brain-Negative Feedback Pathway.
It appears from the above study that sugar lowers cortisol levels, likely in the short term, making us feel more relaxed and comforted for a short time. Ultimately, as Gyllenhammer et al reported, higher sugar results in higher total cortisol, driving abdominal obesity.
Al-Dujaili et al (Feb 2019 Nutrients) performed a small study that showed higher glycemic index diets resulted in higher cortisol levels. The potential for a very unnatural cycle is becoming apparent—high stress driving comfort food eating with cortisol spikes that, reduced with sugar. And repeat. And again.
Break the cycle! As discussed extensively in past articles, I feel a lower glycemic index/lower carbohydrate and higher fat way of eating; the reservation of sugar for special occasions in small amounts is the healthiest relationship you could have with food. And critical to normalizing your cortisol curve.
Regular exercise. Rankin et al (Am J Health Promot. 2013) and Pedersen et al (Nat Rev Endocrinol. 2019), among many others, have shown that staying active reduces stress levels and allows one to be more resilient when stress occurs. Just simple walking, as detailed by Yamada et al (J Am Med Dir Assoc. 2015), improves hormone levels, strength, and quality of life. Regardless of your endurance proclivities, regular, purposeful body movement in a varied manner mixing strength with cardio can help optimize HPA axis function.
Meditation. Dada et al (J Glaucoma. 2018) and Fan et al (Stress Health. 2014) studied numerous biomarkers, including cortisol improvements with meditation.
Massage. Field et al (Int J Neurosci. 2005) likely had very little trouble recruiting subjects for their study. Cortisol reduced by 31%, and the mood-enhancing brain neurotransmitters serotonin and dopamine increased by 28% and 31%, respectively, in those getting a proper rub-down.
Sleep. Even short-term sleep distortion has a measurable effect on cortisol levels. The cumulative effect of poor sleep, like a poor diet, has significant implications on disease development over time. Horotsu et al wrote a tome (Sleep Science. Nov 2015) detailing how stress and sleep interact bi-directionally, sharing many brain and metabolic pathways. Sleep loss and poor sleep quality cause HPA axis activation, thus driving cortisol release.
Similar to the sugar-cortisol interplay, a dysfunctional cycle may develop. Poor sleep, higher cortisol, more poor sleep. Telling someone to get good sleep is akin to telling someone with hypertension to "just have normal blood pressures ."Or a patient with depression, "just be happy ."Insomnia, like the other conditions, is a complex disorder requiring a thorough workup, discussion, and possibly medication.
Gut microbiota. Our microbial ecosystem has developed with us in a symbiotic manner. The numerous functions it serves continue to unfold, but it is well known to interact with our HPA axis. Disorders of our gut flora directly affect the HPA axis, and axis disorders affect our gut flora. Farzi et al (Neurotherapeutics Jan 2018.) did a fascinating study on mice and how gut flora perturbation using antibiotics and gut flora enhancement using probiotics greatly affected stress hormone levels. There is a great deal of writing about prebiotics, probiotics, and the gut benefits of fermented foods. Attempting to optimize this universe of complexity within your colon should occur, perhaps under the direction of someone who understands it. Poop.
Dark chocolate. Like the massage study, there was no trouble with participant recruitment for this Tsang et al (Antioxidants. June 2019) study. Though not a large study, for the 26 slots, I'm told over 35 million applied. They all ate dark chocolate. Some had normal, flavonoid-enriched chocolate, and others ate chocolate with the flavonoid phytonutrients removed. There was a distinct difference in stress hormone levels in the two groups, with the flavonoid eaters having much lower levels. This study has been beneficial to me. "It's medicinal!" I tell my wife. "And yes, I need it melted on my broccoli!" (How much, how often? And where do you find flavonoid chocolate?)
I'm weird. You know this by now. I read about wars, mass destruction, the Holocaust, and many examples of humans at their best and their worst. It gives me perspective about what others have been through and what we are capable of. In October, I ran a 31-mile race when I probably shouldn't have. And I have a lifetime of suffering in the mountains. I do such things primarily to gain perspective through experience and apply it to my life. Perspective on what is possible, that most hardship is way overblown, to be positive, and reframe. Kelly McGonigal discusses this in the book The Upside of Stress. Stress can make you sharp, resilient, driven, and filled with purpose. Simply believing stress is bad for you may elevate cortisol levels more than the same amount of stress reframed into something useful.
Though not easy work, the pursuit of health and wellness demands that we elevate our game. Stress minimization and reframing, restorative sleep, regular body movement, mindfulness, optimal human nutrition, and supplementation are mostly under our control. These strategies can help normalize the brain-adrenal axis and cortisol levels, foster health and wellbeing, and minimize disease risk. Curate for yourselves as you are the best equipped to do it.